Epidemiological and clinical studies have demonstrated an association between depression and increased risk of cardiovascular morbidity and mortality, but the mechanisms are unclear. Understanding how depression leads to cardiovascular disease (CVD) will help clarify the pathophysiology of CVD and develop interventions to decrease the cardiovascular risk associated with depression. Previous studies, including our own, have provided evidence that inflammation may be a key factor. However, detailed mechanisms underlying this neuro-cardiac interaction are unknown. In syntony with emerging evidence on the importance of epigenetic regulation in immune and inflammatory responses, our fundamental hypothesis is that epigenetic mechanisms involved in immune system regulation are important in the link between depression and CVD. Based on our preliminary study which provides strong support to this hypothesis, we aim to identify the differential methylation profiles in leukocytes between major depressive disorder (MDD) cases and controls and further evaluate whether these methylation variations are involved in the pathogenesis of CVD. Specifically, we will perform a genome-wide methylation screening in an existing twin cohort discordant for MDD and a replication in independent cohorts. This will be the first study to explore possible epigenetic modification linking depression to CVD. Clarification of these epigenetic modifications will improve our understanding of key mechanisms underlying brain-heart interactions, and ultimately point to more effective primary prevention strategies for the identification and treatment of individuals at highest risk of CVD.